Exploring the Therapeutic Potential of Modulating Nonsense-mediated MRNA Decay

Overview

Journal RNA

Specialty Molecular Biology

Date 2024 Dec 12

PMID 39667907

Authors

Mary McMahon

Lynne E Maquat

Affiliations

Soon will be listed here.

Abstract

Discovered more than four decades ago, nonsense-mediated mRNA decay (NMD) plays a fundamental role in the regulation of gene expression and is a major contributor to numerous diseases. With advanced technologies, several novel approaches aim to directly circumvent the effects of disease-causing frameshift and nonsense mutations. Additional therapeutics aim to globally dampen the NMD pathway in diseases associated with pathway hyperactivation, one example being Fragile X syndrome. In other cases, therapeutics have been designed to hijack or inhibit the cellular NMD machinery to either activate or obviate transcript-specific NMD by modulating pre-mRNA splicing. Here, we discuss promising approaches employed to regulate NMD for therapeutic purposes and highlight potential challenges in future clinical development. We are optimistic that the future of developing target-specific and global modulators of NMD (inhibitors as well as activators) is bright and will revolutionize the treatment of many genetic disorders, especially those with high unmet medical need.

References

Sun M, Yang Y . Biological functions and applications of circRNAs-next generation of RNA-based therapy. J Mol Cell Biol. 2023; 15(5). PMC: 10708935. DOI: 10.1093/jmcb/mjad031. View

Bharti N, Santos L, Davyt M, Behrmann S, Eichholtz M, Jimenez-Sanchez A . Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations. Nat Commun. 2024; 15(1):2957. PMC: 10997658. DOI: 10.1038/s41467-024-47258-9. View

Huang L, Low A, Damle S, Keenan M, Kuntz S, Murray S . Antisense suppression of the nonsense mediated decay factor Upf3b as a potential treatment for diseases caused by nonsense mutations. Genome Biol. 2018; 19(1):4. PMC: 5769327. DOI: 10.1186/s13059-017-1386-9. View

Karousis E, Muhlemann O . Nonsense-Mediated mRNA Decay Begins Where Translation Ends. Cold Spring Harb Perspect Biol. 2018; 11(2). PMC: 6360860. DOI: 10.1101/cshperspect.a032862. View

Baradaran-Heravi A, Balgi A, Hosseini-Farahabadi S, Choi K, Has C, Roberge M . Effect of small molecule eRF3 degraders on premature termination codon readthrough. Nucleic Acids Res. 2021; 49(7):3692-3708. PMC: 8053119. DOI: 10.1093/nar/gkab194. View

Ni J, Grate L, Donohue J, Preston C, Nobida N, OBrien G . Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev. 2007; 21(6):708-18. PMC: 1820944. DOI: 10.1101/gad.1525507. View

Kim Y, Nomakuchi T, Papaleonidopoulou F, Yang L, Zhang Q, Krainer A . Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy. Nat Commun. 2022; 13(1):2978. PMC: 9142507. DOI: 10.1038/s41467-022-30668-y. View

Kariko K, Muramatsu H, Welsh F, Ludwig J, Kato H, Akira S . Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008; 16(11):1833-40. PMC: 2775451. DOI: 10.1038/mt.2008.200. View

Howard M, Frizzell R, Bedwell D . Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996; 2(4):467-9. DOI: 10.1038/nm0496-467. View

10.

Sharma J, Du M, Wong E, Mutyam V, Li Y, Chen J . A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun. 2021; 12(1):4358. PMC: 8285393. DOI: 10.1038/s41467-021-24575-x. View

11.

Neumann A, Meinke S, Goldammer G, Strauch M, Schubert D, Timmermann B . Alternative splicing coupled mRNA decay shapes the temperature-dependent transcriptome. EMBO Rep. 2020; 21(12):e51369. PMC: 7726792. DOI: 10.15252/embr.202051369. View

12.

Bush J, Aikawa H, Fuerst R, Li Y, Ursu A, Meyer S . Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models. Sci Transl Med. 2021; 13(617):eabd5991. PMC: 9533739. DOI: 10.1126/scitranslmed.abd5991. View

13.

Neil C, Seiler M, Reynolds D, Smith J, Vaillancourt F, Smith P . Reprogramming RNA processing: an emerging therapeutic landscape. Trends Pharmacol Sci. 2022; 43(5):437-454. DOI: 10.1016/j.tips.2022.02.011. View

14.

Saltzman A, Kim Y, Pan Q, Fagnani M, Maquat L, Blencowe B . Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. Mol Cell Biol. 2008; 28(13):4320-30. PMC: 2447145. DOI: 10.1128/MCB.00361-08. View

15.

Komor A, Kim Y, Packer M, Zuris J, Liu D . Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016; 533(7603):420-4. PMC: 4873371. DOI: 10.1038/nature17946. View

16.

Gebauer F, Hentze M . Molecular mechanisms of translational control. Nat Rev Mol Cell Biol. 2004; 5(10):827-35. PMC: 7097087. DOI: 10.1038/nrm1488. View

17.

Rowe S, Zuckerman J, Dorgan D, Lascano J, McCoy K, Jain M . Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. J Cyst Fibros. 2023; 22(4):656-664. PMC: 10524666. DOI: 10.1016/j.jcf.2023.04.008. View

18.

Weischenfeldt J, Waage J, Tian G, Zhao J, Damgaard I, Jakobsen J . Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns. Genome Biol. 2012; 13(5):R35. PMC: 3446288. DOI: 10.1186/gb-2012-13-5-r35. View

19.

Lucas F, Abraham Versloot R, Yakovlieva L, Walvoort M, Maglia G . Protein identification by nanopore peptide profiling. Nat Commun. 2021; 12(1):5795. PMC: 8490355. DOI: 10.1038/s41467-021-26046-9. View

20.

Riedmayr L, Hinrichsmeyer K, Thalhammer S, Mittas D, Karguth N, Otify D . mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy. Nat Commun. 2023; 14(1):6578. PMC: 10584818. DOI: 10.1038/s41467-023-42386-0. View